Grb2 is an adaptor protein that functions downstream of the insulin and IGF-I receptors. Grb2 binds to the She isoforms and plays a key role in insulin/IGF-l-mediated mitogenic events. There are some data suggesting that reducing Grb2 expression levels may decrease aging-associated tumor progression and extend lifespan. First, enhanced expression of Grb2 accelerates tumor development. In contrast, reducing Grb2 expression by gene targeting retards mammary carcinomas induced by polyomavirus middle T antigen in whole animals. Furthermore, disruption of the gene expression of p66Shc, one of the She isoforms that interacts with Grb2, leads to increased resistance to oxidative stress and extended lifespan. Finally, caloric restriction, which has been conclusively and reproducibly shown to increase maximum lifespan while attenuating the development of age-associated pathology such as tumor progression, significantly reduced the expression levels of Grb2. Based on these findings, we hypothesize that reducing the expression levels of Grb2 in mice increases lifespan by delaying tumor progression and increasing resistance to oxidative stress. To test this hypothesis, we propose the following Specific Aims: 1. To determine whether reducing Grb2 expression enhances resistance to oxidative stress in mice. 2. To determine whether reducing Grb2 expression levels inhibits tumor incidence in mice. 3. To determine whether reducing Grb2 expression in mice leads to extended lifespan. Results from these studies will allow us to determine if the mice with reduced levels of Grb2 expression are a novel animal model to study aging. [unreadable] [unreadable]